Jeannette Y. Wick, RPh, MBA, FASCP
Most clinicians deem treatment response variability among direct oral anticoagulants—which include direct thrombin inhibitors and factor Xa inhibitors—clinically insignificant.
Response has appeared consistent between patients and during treatment, or at least only slightly variable.
Dabigatran is a direct thrombin (factor II) inhibitor with a newly available reversal agent
, while rivaroxaban and apixaban are the 2 most frequently prescribed factor Xa inhibitors.
The medications are dosed based on indication (atrial fibrillation or venous thromboembolism), patient characteristics (age, gender, body weight, and drug-drug interactions), and consideration of renal and liver function.
A study published online in Thrombosis Research
indicates that drug levels vary widely between and even within patients.
In this multicenter study, the researchers enrolled 330 patients receiving dabigatran, rivaroxaban, and apixaban. They measured patient response using diluted-thrombin-time for dabigatran and anti-factor Xa for rivaroxaban and apixaban.
Dabigatran concentrations varied more than 20-fold, while concentrations varied nearly 15-fold for rivaroxaban and 7-fold for apixaban. Trough levels varied more than peak levels.
Patient metabolism is suspected to be a stronger driver of interindividual variability than variable absorption.
Drug levels also varied considerably in dabigatran patients (55%), but less so in rivaroxaban (33%) and apixaban (19%) patients. Dabigatran, rivaroxaban, and apixaban are renally eliminated to varying degrees (80%, 35%, and 27%, respectfully).
Hemorrhage risk was elevated in patients receiving dabigatran who had creatinine clearances slightly above the label-recommended minimum of 30 mL/min. However, creatinine clearance alone does not explain the range of patient variability.
Dabigatran’s trough plasma concentrations were more closely associated with relative risk of hemorrhage than with relative risk of ischemic stroke. This suggests that response variability may be a safety concern, rather than an efficacy issue.
The study authors recommended establishing drug-specific cutoffs to prevent safety events and promote efficacy.
The likelihood of variable elimination calls for careful discontinuation of these drugs before surgery, followed by perioperative drug levels.
Confounding factors are insufficiently studied to accurately predict the risk of bleeding.